Somatostatin (also known as growth hormone inhibiting hormone or GHIH) is a peptide hormone produced in the hypothalamus as well as certain portions of the digestive system. Somatostatin is generally involved in regulation of the endocrine system via interactions with G-protein-coupled somatostatin receptors. This somatostatin-based signaling cascade leads to a number of actions spread throughout the body.
Relevant to aspects of the present invention, somatostatin is known to inhibit the release of growth hormone and thyroid stimulating hormone from the anterior pituitary. (Patel Y C and Srikant C B, Somatostatin and its receptors Adv Mol Cell Endocrinol, 1999. 3 43-73). Other hormones inhibited by somatostatin include insulin, glucagon, secretin, gastrin, pepsin, maletin, etc. (Patel Y C and Srikant C B Somatostatin and its receptors Adv Mol Cell Endocrinol, 1999. 3 43-73). The ability of somatostatin to regulate so many factors/hormones necessary for growth and utilization of food has made somatostatin a central target for controlling animal growth in the animal husbandry field, i.e., inhibiting somatostatin results in increased levels of growth hormone being present in a target animal and thereby results in animals with enhanced capacity to produce milk, to provide greater amounts of meat, etc.
In particular, immunization of animals to somatostatin has been recognized as a means of neutralizing somatostatin in a target animal and thereby removing somatostatin's normal inhibitory effects on various aspects of the animal's productivity, e.g., milk production in a dairy cow. Reichlin S., ed., 1987, Somatostatin, Basic and Clinical Status, Plenum Press, New York (pp 3-50, 121-136, 146-156, 169-182, 221-228, 267-274) Spencer G. S., 1985, Hormonal systems regulating growth, review, Livestock Production Science, 12, 31-46. Importantly, these somatostatin-based immunization procedures avoid the direct use of anabolic hormones, e.g., growth hormone, and the like, in the animal and allow for small changes in the concentration of the endogenous anabolic factors and thereby provide ecologically pure food products.
Somatostatin is known to have a relatively short half-life in the blood. In order to enhance the immunologic effects of somatostatin, immunization protocols have been developed to enhance the protein's half-life by conjugating somatostatin to target carrier proteins. These conjugated somatostatin proteins are designed to have increased half-life and increased antigenicity in the blood and therefore provide enhanced benefits (especially in light of the cost of preparing somatostatin). For example, chimeric somatostatin proteins are disclosed in U.S. Pat. No. 6,316,004, (and corresponding European Patent EP0645454) where various conjugated somatostatin-containing proteins are shown to have increased antigenicity and function with regard to productivity of farm animals as compared to other conventional immunization or anabolic hormone-based procedures.
However, lower dose, higher antigenicity based immunization compositions and procedures are needed to improve overall productivity and timeliness in the animal husbandry field. The present invention is directed toward providing these more antigenic and functionally active somatostatin-based immunization compounds, compositions and procedures.
Against this backdrop the following disclosure is provided.